An increasing prevalence of resistant viruses and the presence of latently infected CD4+ cells in patients receiving highly active antiretroviral therapy have become an impediment to drug therapy. One evolving therapy to combat HIV infection is gene therapy, which involves the introduction of anti-HIV genes to inhibit viral gene expression thereby limiting HIV replication. Many different anti-HIV gene therapy approaches have been established to inhibit virus replication and these strategies have been propelled to the forefront of developmental therapies for HIV infection. Although these studies are encouraging, development of a safe and efficient vector to deliver the antiviral genes still remains a challenge. The current vectors utilized in clinical trials for HIV gene therapy are inefficient for the main reason that they can not be propagated in non-dividing cells or their genome does not efficiently integrate into host DNA. Vectors based on lentiviruses such as HIV are promising since they can infect both dividing and non-dividing cells. Although the feasibility of lentiviruses in human gene therapy is still being explored, lentivirus vectors suffer from the potential risk of causing disease in humans. The safety concern will remain in the public eye even with third generation HIV vectors where the possibility of creating a wild type HIV is excluded. This is further complicated by the recent observation of the development of liver tumors in mice treated intravenously with a lentivirus vector. Foamy viruses have several inherent features that make them an ideal vector system. These viruses do not cause disease in an infected individual and have a broad host range with respect to cell types and species. Integration analysis of foamy virus vector genome into host chromosome reveals a reduced risk for mutating or activating cellular genes when compared to lentiviruses, corroborating the non-pathogenic phenotype of foamy virus infection. We have developed an efficient foamy virus vector system for the present study. The current proposal is a continuation of the use of SFV-1 for effective antiviral therapy against immunodeficiency viruses using novel severe combined immunodeficiency (SCID) mice (NOD/LtSz-scid IL2Rgnull). The NOD/LtSz-scid IL2Rgnull mouse allows the efficient repopulation of human lymphocytes and subsequently eases virus challenge studies. Studies from this proposal will help devise protocols for SFV-1 vector mediated gene therapy against HIV infection in humans